Despite the success of combined antiretroviral therapy (cART) to diminish peripheral infection, HIV-1 can establish an infection in the central nervous system (CNS), resulting in the development of cognitive, behavioral, and motor deficits associated with HIV-1 associated neurocognitive disorders (HAND). Once infected, the CNS acts as a viral reservoir that is difficult to treat and eradicate. Mononuclear phagocytes (MPs, e.g., perivascular macrophages and microglia) are important reservoirs in the immune-privileged CNS. The proposed studies are designed to address the unique dynamics of HIV infection in CNS and explore novel therapeutic strategies that target MPs, ensure viable delivery across the blood-brain barrier (BBB) to eliminate the HIV reservoir and reduce inflammation. HIV-induced activation and viral replication in MPs are relevant targets that will be approached through multiple pharmacological agents. Three unique and independently identified strategies will be investigated as novel therapeutic agents to reduce HIV replication within MPs: JAK inhibitors that block/interrupt the activation state of MPs and that can reduce inflammation, MP-specific ribonucleoside chain terminators and their phosphate prodrugs for increased delivery to the CNS, and NADPH oxidase inhibitors that are known to cross the BBB which indirectly could reduce NF8- dependent HIV-1 transcription. Selected therapeutic agents will be analyzed for their in vitro antiviral potency, and to assess biochemistry, toxicology, and cellular pharmacology parameters. Specific small molecule candidates which fulfill potency criteria will be evaluated in vivo to assess CNS pharmacology and response (including behavior and pathology) to treatment using two distinct retrovirus CNS animal models we have previously established: SCID mouse model intracranially injected with HIV-1 infected MPs, and CD4+ depleted macaque model infected with SIVmac239. Results from these studies will identify new adjunctive therapeutic strategies which together with current cART could provide improved targeted therapy to MPs. The ultimate goal is to suppress virus and eliminate these HIV-1 reservoirs in the CNS that should lead to improved treatments to reduce risk(s) of developing HAND.